Epidemiological, clinical, and laboratory studies have suggested an interaction between opiods and stress, and I have proposed a role for the hypothalamic-pituitary-adrenal (HPA) axis in these interactions. Recently, I have demonstrated that chronic morphine treatment produces profound and long-lasting changes in the pituitary-adrenal responses to restraint stress. HPA axis activity in rats undergoing acute morphine withdrawal resembles that observed in depressed patients, whereas HPA axis activity in rats undergoing chronic morphine withdrawal mimics that observed in patients suffering from post-traumatic stress disorder (PTSD). The studies proposed herein will integrate physiological, pharmacological, and endocrinological approaches to examine the development and recovery of morphine-induced changes in HPA axis function. The pattern, extent, and time course of changes in various neurohormone and receptor systems that are involved in and necessary for HPA axis function under basal and stress conditions will be examined in morphine-dependent rats. The role of corticosterone hypersecretion, altered sensitivity of negative feedback systems, and recruitment of facilitatory neuronal pathways in the modified stress responses observed in morphine-treated animals will also be examined. These studies may elucidate the role of altered HPA axis function in the neurobiology of drug dependence, depression, and PTSD.